1. Area of the Art
The invention relates generally to the regulation of cell movement and specifically to the inhibition of smooth muscle cell (SMC) movement by Tenascin-C peptides.
2. Description of the Prior Art
Throughout this application, various references are referred to within parentheses. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains. Full bibliographic citation for these references may be found at the end of this application, preceding the claims.
Neointima formation is a leading cause of the pathogenesis of vascular diseases such as atherosclerosis, restenosis following percutaneous transluminal coronary angioplasty (PTCA), and vein bypass atherosclerosis. Migration of vascular smooth muscle cells from media to intima plays a critical role in neointima formation (1-3). After surgical injury to the arterial integrity, activated smooth muscle cells migrate and then proliferate in the neointima (4). Accumulation of SMCs and deposition of an extracellular matrix lead to a hemodynamically compromising neointimal lesion, which is developed in a fraction of the time that is needed for the development of the primary atherosclerotic lesion (5). To prevent intimal hyperplasia, restenosis and atherosclerosis, the rapid accumulation of SMCs in the neointima must be inhibited (6).
Excessive SMC proliferation and migration occur as a result of growth factors produced by cellular constituents in the blood and the damaged arterial vessel wall which mediates the proliferation of SMCs in vascular restenosis. SMC migration may be activated by chemotactic agents, such as PDGF-BB and angiotensin II, and chemokinetic agents such as PDGF. Antibodies to growth factor PDGF may inhibit neointimal smooth muscle cell accumulation after angioplasty (6).
The SMC migration is mediated by interaction of SMC surface receptors and the extracellular matrix. The process of cell attachment to the matrix is frequently mediated by a family of cell-surface receptors called integrins (7). These receptors constitute a family of proteins with share structural characteristics of noncovalent, heterodimeric glycoprotein complexes including .alpha. and .beta. subunits. Integrin receptors are believed to form a link between the extracellular and intracellular environments and to affect cellular behavior by transmitting extracelluar signals to the intracellular compartment.
Some integrins recognize and bind to specific amino acid sequences within matrix macromolecules. For example, the integrin receptors on a number of cell types recognize an arginine-glycine-aspartic acid sequence (RGD) within the cell-binding domain of the extracelluar matrix proteins (8). The smooth muscle cell has at least six of these RGD-dependent integrins, including the fibronectin receptor .alpha..sub.5 .beta..sub.1, the vitronectin receptor .alpha..sub.v .beta..sub.3, and the platelet glycoprotein IIb/IIIa, .alpha..sub.IIb .beta..sub.IIIa. Peptides that block integrin .alpha..sub.v .beta..sub.3 can inhibit neointimal hyperplasia (9).
It has been observed that chemotactic factors, including PDGF-BB and angiotensin II, markedly induce Tenascin-C gene expression in SMCs (10, 11). Tenascin-C is an oligomeric glycoprotein composed of multiple domains that has been implicated in cell migration (12-18). Human, mouse, and chicken Tenascin-C contain a cysteine-rich segment at their amino termini through which the six Tenascin-C monomers link into a hexamer. This segment is followed by epidermal growth factor-like repeats, fibronectin-type III repeats (FN-L) and a globular carboxyl terminus, homologous to fibrinogen (Fbg-L) (19). These domains mediate the interaction between the Tenascin-C molecule and cells. For example, endothelial cells interact with Tenascin-C through its fibrinogen-like domain (20), whereas the FN-L domain of Tenascin-C mediates interaction with fibroblast (21).
However, the interaction of SMCs with Tenascin-C is unknown. Particularly, the specific domain of Tenascin-C that mediates its interaction with SMCs is unknown. It is desirable to study the molecular mechanism of Tenascin-C-SMC interactions, and therefore to provide agents that inhibit the migration of smooth muscle cells that are useful in the treatment and prevention of intimal hyperplasia, restenosis and atherosclerosis.